NK105, a paclitaxel-incorporating micellar nanoparticle, is a more potent radiosensitising agent compared to free paclitaxel

Abstract

NK105 is a micellar nanoparticle formulation designed to enhance the delivery of paclitaxel (PTX) to solid tumours. It has been reported to exert antitumour activity in vivo and to have reduced neurotoxicity as compared to that of free PTX. The purpose of this study was to investigate the radiosensitising effect of NK105 in comparison with that of PTX. Lewis lung carcinoma (LLC)-bearing mice were administered a single intravenous (i.v.) injection of PTX or NK105; 24 h after the drug administration, a proportion of the mice received radiation to the tumour site or lung fields. Then, the antitumour activity and lung toxicity were evaluated. In one subset of mice, the tumours were excised and specimens were prepared for analysis of the cell cycle distribution by flow cytometry. Combined NK105 treatment with radiation yielded significant superior antitumour activity as compared to combined PTX treatment with radiation (P ¼ 0.0277). On the other hand, a histopathological study of lung sections revealed no significant difference in histopathological changes between mice treated with PTX and radiation and those treated with NK105 and radiation. Flowcytometric analysis showed that NK105-treated LLC tumour cells showed more severe arrest at the G2/M phase as compared to PTX-treated tumour cells. The superior radiosensitising activity of NK105 was thus considered to be attributable to the more severe cell cycle arrest at the G2/M phase induced by NK105 as compared to that induced by free PTX. The present study results suggest that further clinical trials are warranted to determine the efficacy and feasibility of combined NK105 therapy with radiation.

Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination

“…The NK105 was supplied as a powder formulation and contained 4.1% (w/w) paclitaxel, which had been prepared as reported previously. (31,32) Briefly, polymeric micellar particles were formed by the self-association of amphiphilic block copolymers in an aqueous medium. The NK105 polymer was generated using PEG as the hydrophilic segment and modified polyaspartate as the hydrophobic segment.…”

“…Previous studies in animal cancer models have reported that intravenous administration of NK105 results in enhanced antitumor effects and reduced toxicity compared with PTX-Cre. (31,32) The safety and pharmacokinetic advantages of NK105 in humans were demonstrated in a Phase I trial, (33) whereas a Phase II trial of NK105 for advanced gastric cancer with failure of first-line chemotherapy reported an overall response rate of 25% and median overall survival of 14.4 months. (34) The intraperitoneal administration of nanoparticulate anticancer agents for the treatment of peritoneal dissemination has not been investigated extensively, despite the existence of data indicating the potency of this type of treatment.…”

“…Previous studies in animal cancer models have reported that intravenous administration of NK105 results in enhanced antitumor effects and reduced toxicity compared with PTX-Cre. (31,32) The safety and pharmacokinetic advantages of NK105 in humans were demonstrated in a Phase I …”

Synthesis, characterization, and biological evaluation of poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate

“…Polymeric micelles comprising block hydrophilic polyethylene glycol and hydrophobically modified poly-aspartate, poly-glutamate, or poly(d,l-lactide) have been used for encapsulating hydrophobic drugs. These are capable of forming nanoparticles when loaded with paclitaxel (PTX), [9][10][11][12] doxorubicin, 13,14 and cisplatin. [15][16][17] The goal of the study reported here was to design a nonblock polymer capable of supporting high drug loading and forming a nanoparticle in aqueous environments.…”

Formulation and Evaluation of Paclitaxel-Loaded Polymeric Nanoparticles Composed of Polyethylene Glycol and Polylactic Acid Block Copolymer

“…46,47) However, due to the instability of these conventional polymeric micelles in the systemic circulation, the encapsulated drug was shown to be rapidly released in the systemic circulation. Therefore, the chemical conjugation of doxorubicin to a diblock copolymer 48,49) or chemical introduction of a hydrophobic group to paclitaxel 50,51) was necessary to more stably incorporate these drugs into, and to reduce their excess release from, polymeric micelles in the systemic circulation. Although these structural properties of PN-PTX successfully provided stable incorporation of around 80% of PTX in the systemic circulation, at the same time the PTX release from PN-PTX within tumor tissues was suggested to be insufficient, leading to poor in vivo anti-tumor activity (Fig.…”